Immunotherapy using complement activating antibodies specific for tumor antigens has not yielded satisfactory results in the clinic. Complement inhibitors expressed on tumor cells (often at elevated levels) promote tumorigenesis and are an important factor in the resistance of tumor cells to antibody-mediated immunotherapy. We hypothesize that downregulation of the expression of complement inhibitory proteins on the surface of tumor cells will increase sensitivity of tumor cells to anti-MUCI (a bladder cancerassociated antigen) antibody-mediated immunotherapy and may also enhance the outcome of a normally ineffective immune response. It is proposed to use a clinically relevant syngeneic MUC1 transgenic model of bladder cancer to investigate the role of complement inhibitors in tumor immunity and in the resistance of tumor cells to anti-MUC1 antibody therapy in the context of immune sufficiency, tolerance and autoimmunity. The expression of complement inhibitors will be modulated by RNAi. The proposed studies have the potential to lead to the development of new immunotherapy strategies for the treatment of bladder cancer